The investigational drug lasofoxifene decreases the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis, according to a report.
The nonsteroidal selective estrogen-receptor modulator (SERM) also reduces the risk of ER-positive breast cancer, major coronary heart disease events, and stroke without raising the risk of endometrial cancer or hyperplasia.
Like other SERMs, lasofoxifene raises the risk of venous thromboembolism and increases the rate of hot flushes and leg cramps, wrote Dr. Steven R. Cummings of California Pacific Medical Center Research Institute, San Francisco, and his associates in the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) study.
Taken together, these findings seem to indicate that lasofoxifene performs somewhat better than do other SERMs such as raloxifene, and also has advantages over hormone therapy, tamoxifen, and tibolone.
However, in an editorial accompanying this report, Dr. Carolyn Becker of the division of endocrinology, diabetes, and hypertension at Brigham and Women's Hospital, Boston, argued that the drug “offers no major clinically important benefits over raloxifene for the skeleton, breast, heart, or reproductive tract.
“Given the plethora of drugs currently available for osteoporosis, studies of new agents should show clear benefits over existing agents,” she wrote. Results of the PEARL study do not do so, Dr. Becker added.
Dr. Cummings and his colleagues performed the international, randomized, placebo-controlled PEARL study in 8,556 women aged 59-80 years who had a bone mineral density T score of −2.5 or less at the lumbar spine or femoral neck. A total of 28% already had at least one vertebral fracture at baseline.
After 5 years of follow-up, women who received 0.5 mg per day of lasofoxifene showed a 42% reduction in relative risk for vertebral fractures and a 24% reduction in relative risk for nonvertebral fractures, compared with those who received placebo.
Bone density at the lumbar spine, femoral neck, and total hip improved by about 3% with the active drug, the investigators said (N. Engl. J. Med. 2010;362:686-96).
This decrease in risk of vertebral fractures is comparable with that reported in women taking raloxifene, estrogen therapy, oral bisphosphonates, and tibolone.
The decrease in risk of nonvertebral fractures also is similar to that observed in women taking other antiresorptive therapies, and it stands in contrast to raloxifene's inability to reduce this risk, they said.
However, Dr. Becker noted in her editorial that nearly all the reduction in risk for nonvertebral fractures could be attributed to forearm and wrist fractures. “A significant effect in the overall group was not evident until 5 years, and absolute risk reductions were very small.
“On balance, lasofoxifene seems to offer little, if any, advantage over raloxifene as an agent against osteoporosis,” she said (N. Engl. J. Med. 2010;362:752-4).
Lasofoxifene also reduced the risk of ER-positive breast cancer by 85%, compared with placebo. Although this finding is “impressive,” it is similar to the risk reduction reported for raloxifene, Dr. Becker added.
Lasofoxifene was associated with a 32% reduction in relative risk of coronary heart disease events (5.1 cases per 1,000 person-years) and a 36% reduction in relative risk of stroke (2.5 cases per 1,000 person-years), compared with placebo (7.5 and 3.9 cases per 1,000 person-years, respectively), Dr. Cummings and his associates said.
However, Dr. Becker noted that the number of these events was quite small, and there were no differences in rates of fatal stroke. “Although the cardiovascular benefits reported in the PEARL trial seem impressive, one would need to treat 492 patients for 1 year to prevent a single major coronary event,” she said.
The PEARL investigators said that lasofoxifene raised the risk of venous thromboembolism to a similar degree as do raloxifene, tamoxifen, and oral estrogen therapies. Like these agents, lasofoxifene also significantly increased the rate of hot flushes and leg cramps. It did not raise the risk of endometrial cancer or endometrial hyperplasia.
Dr. Becker countered that although the increase in absolute risk of venous thromboembolism was small, lasofoxifene more than doubled the relative risk.
In addition, rates of uterine polyps, endometrial hypertrophy, and vaginal candidiasis all were significantly higher than with placebo, she said.
Pfizer submitted a new drug application to the Food and Drug Administration in 2007, and in 2008 an advisory panel voted 9-3 that the benefits of the SERM outweighed this risk in postmenopausal women with osteoporosis. The FDA has not yet issued a decision.
Disclosures: The PEARL study was funded by Pfizer, manufacturer of lasofoxifene. Dr. Cummings reported receiving consulting fees from Amgen, Eli Lilly, GlaxoSmithKline, and Organon, lecture fees from Eli Lilly and Novartis, and grant support from Amgen, Pfizer, and Eli Lilly. Dr. Becker's financial disclosures are available with the text of the article at NEJM.org